Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Brain Behav Immun ; 101: 318-332, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35065198

RESUMEN

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. Recently we showed that activation of the purinergic P2X7 receptors is necessary and sufficient to convert maternal immune activation (MIA) to ASD-like features in male offspring mice. Our aim was to further substantiate these findings and identify downstream signaling pathways coupled to P2X7 upon MIA. Maternal treatment with the NLRP3 antagonist MCC950 and a neutralising IL-1ß antibody during pregnancy counteracted the development of autistic characteristics in offspring mice. We also explored time-dependent changes of a widespread cytokine and chemokine profile in maternal blood and fetal brain samples of poly(I:C)/saline-treated dams. MIA-induced increases in plasma IL-1ß, RANTES, MCP-1, and fetal brain IL-1ß, IL-2, IL-6, MCP-1 concentrations are regulated by the P2X7/NLRP3 pathway. Offspring treatment with the selective P2X7 receptor antagonist JNJ47965567 was effective in the prevention of autism-like behavior in mice using a repeated dosing protocol. Our results highlight that in addition to P2X7, NLRP3, as well as inflammatory cytokines, may also be potential biomarkers and therapeutic targets of social deficits and repetitive behaviors observed in autism spectrum disorder.


Asunto(s)
Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Receptores Purinérgicos P2X7 , Animales , Trastorno Autístico/genética , Conducta Animal , Citocinas , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fenotipo , Embarazo , Receptores Purinérgicos P2X7/genética
2.
Bioorg Med Chem Lett ; 67: 128714, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35367591

RESUMEN

The systemic use of GABAB orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABAB positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold. Further elaborating the scaffold, we identified several in vitro and in vivo active compounds.


Asunto(s)
Agonistas de Receptores GABA-B , Receptores de GABA-B , Regulación Alostérica , Baclofeno , Agonistas de Receptores GABA-B/farmacología , Quinazolinas/farmacología
3.
Bioorg Med Chem Lett ; 29(20): 126643, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31492518

RESUMEN

To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.


Asunto(s)
Amidas/química , Antagonistas de los Receptores Histamínicos/química , Receptores Histamínicos H3/metabolismo , Amidas/farmacología , Animales , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Masculino , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Muscarínicos/química , Solubilidad , Esteroides/química
4.
Bioorg Med Chem Lett ; 27(19): 4525-4530, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28888822

RESUMEN

Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.


Asunto(s)
Descubrimiento de Drogas , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Agonistas de los Receptores Histamínicos/síntesis química , Agonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Estructura Molecular , Ratas , Relación Estructura-Actividad
5.
Pharmaceuticals (Basel) ; 17(7)2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-39065788

RESUMEN

The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25-1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates.

6.
J Med Chem ; 67(1): 643-673, 2024 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-38165765

RESUMEN

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.


Asunto(s)
Arginina Vasopresina , Receptores de Vasopresinas , Arginina Vasopresina/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico
7.
J Med Chem ; 67(5): 3643-3667, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38393759

RESUMEN

Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.


Asunto(s)
Antagonistas de los Receptores Histamínicos H3 , Receptores Histamínicos H3 , Ratas , Humanos , Animales , Histamina , Agonismo Inverso de Drogas , Receptores Histamínicos H3/metabolismo , Simulación del Acoplamiento Molecular , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Esteroides , Microsomas Hepáticos/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacología , Antagonistas de los Receptores Histamínicos
8.
ACS Med Chem Lett ; 15(3): 396-405, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38505850

RESUMEN

Selecting a known HTS hit with the pyrazolo[1,5-a]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABAB positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative (34). This lead candidate offers the possibility to improve potency without drastically inflating the physicochemical properties. Although the discovery of the novel carboxyl feature was surprising, it turned out to be an important element of the GABAB PAM pharmacophore that can be perfectly explained based on the new protein structures. Rationalizing the binding mode of 34, we analyzed the intersubunit PAM binding site of GABAB receptor using the publicly available experimental structures.

9.
Sci Rep ; 12(1): 8168, 2022 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35581280

RESUMEN

The human mu rhythm has been suggested to represent an important function in information processing. Rodent homologue rhythms have been assumed though no study has investigated them from the cognitive aspect yet. As voluntary goal-directed movements induce the desynchronization of mu rhythm, we aimed at exploring whether the response-related brain activity during the touchscreen visual discrimination (VD) task is suitable to detect sensorimotor rhythms and their change under cognitive impairment. Different doses of scopolamine or MK-801 were injected subcutaneously to rats, and epidural electroencephalogram (EEG) was recorded during task performance. Arciform ~ 10 Hz oscillations appeared during visual processing, then two characteristic alpha/beta desynchronization-resynchronization patterns emerged mainly above the sensorimotor areas, serving presumably different motor functions. Beyond causing cognitive impairment, both drugs supressed the touch-related upper alpha (10-15 Hz) reactivity for desynchronization. Reaction time predominantly correlated positively with movement-related alpha and beta power both in normal and impaired conditions. These results support the existence of a mu homologue rodent rhythm whose upper alpha component appeared to be modulated by cholinergic and glutamatergic mechanisms and its power change might indicate a potential EEG correlate of processing speed. The VD task can be utilized for the investigation of sensorimotor rhythms in rats.


Asunto(s)
Maleato de Dizocilpina , Escopolamina , Animales , Ritmo beta , Maleato de Dizocilpina/farmacología , Electroencefalografía , Movimiento , Ratas , Escopolamina/farmacología , Percepción Visual
10.
Front Vet Sci ; 9: 785805, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35280140

RESUMEN

For a long time, oxytocin has been thought to have a generally positive effect on social cognition and prosocial behavior; however, recent results suggested that oxytocin has beneficial effects only under certain conditions. The aim of the present study was to explore potential associations between social competence and the effect of intranasal oxytocin on the social behavior of laboratory beagle dogs. We expected oxytocin treatment to have a more pronounced positive effect on dogs with lower baseline performance in a social test battery. Thirty-six adult dogs of both sexes received 32 IU intranasal oxytocin and physiological saline (placebo) treatment in a double-blind, cross-over design, with 17-20 days between the two sessions. Forty minutes after the treatment, dogs participated in a social test battery consisting of eight situations. The situations were carried out within one session and took 20-30 min to complete. Principal component analysis on the coded behaviors identified four components (Willingness to interact, Preference for social contact, Non-aversive response to nonsocial threat, and Non-aversive response to social threat). The subjects' behavior during the placebo condition was used to assess their baseline performance. We found that oxytocin treatment had a differential effect on the behavior depending on the baseline performance of the individuals in all components, but only two treatment × baseline performance interactions remained significant in a less sensitive analysis. In accordance with our hypothesis, oxytocin administration increased dogs' contact seeking and affiliative behaviors toward humans but only for those with low baseline performance. Dogs with low baseline performance also showed significantly more positive (friendly) reactions to social threat after oxytocin administration than after placebo, while for dogs with high baseline performance, oxytocin administration led to a more negative (fearful) reaction. These results indicate that similar to those on humans, the effects of oxytocin on dogs' social behavior are not universally positive but are constrained by individual characteristics and the context. Nevertheless, oxytocin administration has the potential to improve the social behavior of laboratory beagle dogs that are socially less proficient when interacting with humans, which could have both applied and animal welfare implications.

11.
Eur J Pharmacol ; 916: 174621, 2022 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-34965389

RESUMEN

The histamine H3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0-9.2 nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.


Asunto(s)
Receptores Histamínicos H3 , Animales , Cognición , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Histamina/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Ratas , Receptores Histamínicos H3/metabolismo
12.
Physiol Rep ; 9(21): e15088, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34762352

RESUMEN

Neuronal networks cause changes in behaviorally important information processing through the vesicular release of neurotransmitters governed by the rate and timing of action potentials (APs). Herein, we provide evidence that dopamine (DA), nonquantally released from the cytoplasm, may exert similar effects in vivo. In mouse slice preparations, (+/-)-3,4-methylenedioxy-methamphetamine (MDMA, or ecstasy) and ß-phenylethylamine (ß-PEA)-induced DA release in the striatum and nucleus accumbens (NAc), two regions of the brain involved in reward-driven and social behavior and inhibited the axonal stimulation-induced release of tritiated acetylcholine ([3 H]ACh) in the striatum. The DA transporter (DAT) inhibitor (GBR-12909) prevented MDMA and ß-PEA from causing DA release. GBR-12909 could also restore some of the stimulated acetylcholine release reduced by MDMA or ß-PEA in the striatum confirming the fundamental role of DAT. In addition, hypothermia could prevent the ß-PEA-induced release in the striatum and in the NAc. Sulpiride, a D2 receptor antagonist, also prevented the inhibitory effects of MDMA or ß-PEA on stimulated ACh release, suggesting they act indirectly via binding of DA. Reflecting the neurochemical interactions in brain slices at higher system level, MDMA altered the social behavior of rats by preferentially enhancing passive social behavior. Similar to the in vitro effects, GBR-12909 treatment reversed specific elements of the MDMA-induced changes in behavior, such as passive social behavior, while left others including social play unchanged. The changes in behavior by the high level of extracellular DA-- a significant amount originating from cytoplasmic release--suggest that in addition to digital computation through synapses, the brain also uses analog communication, such as DA signaling, to mediate some elements of complex behaviors, but in a much longer time scale.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Transducción de Señal , Conducta Social , Animales , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacología , Masculino , Ratones , N-Metil-3,4-metilenodioxianfetamina/farmacología , Núcleo Accumbens/citología , Núcleo Accumbens/metabolismo , Fenetilaminas/farmacología , Psicotrópicos/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacología
13.
Psychopharmacology (Berl) ; 238(9): 2381-2392, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34264367

RESUMEN

RATIONALE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. OBJECTIVES: The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. METHODS: To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. RESULTS: Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. CONCLUSIONS: In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.


Asunto(s)
Trastorno del Espectro Autista , Piperazinas/uso terapéutico , Efectos Tardíos de la Exposición Prenatal , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Embarazo , Ratas , Ratas Wistar , Ácido Valproico/farmacología
14.
Biomolecules ; 11(1)2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33466844

RESUMEN

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.


Asunto(s)
Investigación Biomédica , Enfermedades del Sistema Nervioso Central/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D3/metabolismo , Investigación Biomédica Traslacional , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/química
15.
J Neurosci Methods ; 343: 108841, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32621917

RESUMEN

BACKGROUND: The social approach and social novelty tests utilizing the three-chamber apparatus are widely accepted to measure social behavior of rodents. The LABORAS™ system offers a possibility to assess sociability of mice in a reliable and objective manner. NEW METHOD: We assessed the capability of the LABORAS™ sociability cage and algorithm (2.6.6) to detect social behaviors in mice. Furthermore, we investigated whether the system is able to detect various levels of sociability due to genetic background or after pharmacological treatments. RESULTS: By comparing manual scoring with various detection zone settings of the automated registration, the most fitting algorithm with a detection zone radius of 90 mm was identified. When different strains were investigated, C57Bl/6 J and NMRI mice proved to be social, while CD1 mice were found asocial. The system was able to detect the sociability increasing effect of R-baclofen (0.5 mg/kg i.p.) and oxytocin (12 ng i.c.v.) in asocial CD1 mice. The negative control PCP impaired social behavior of C57Bl/6 J mice (1 mg/kg i.p.) and increased social avoidance in CD1 mice (0.3 mg/kg i.p.). COMPARISON WITH EXISTING METHOD(S): This setup, in contrast to video frame analysis softwares, determines signal changes caused by movements of rodents allowing accurate detection and analysis of trajectories. Parallel automated measurements also allow replacing time and labor intensive, highly subjective human observational work. CONCLUSIONS: The set-up provides a fast and reliable method to examine social behavior of mice in the three-chamber apparatus. The system is capable of detecting pro or antisocial activity of pharmacological agents.


Asunto(s)
Algoritmos , Conducta Social , Animales , Conducta Animal , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos
16.
Wiley Interdiscip Rev Cogn Sci ; 10(4): e1495, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30762306

RESUMEN

Selecting appropriate animal models for a particular human phenomenon is a difficult but important challenge. The difficulty lies in finding animal behaviors that are not only sufficiently relevant and analog to the complex human symptoms (face validity) but also have similar underlying biological and etiological mechanisms (translational or construct validity), and have "human-like" responses to treatment (predictive validity). Over the past several years, the domestic dog (Canis familiaris) has become increasingly proposed as a model for comparative and translational neuroscience. In parallel to the recent advances in canine behavior research, dogs have also been proposed as a model of many human neuropsychiatric conditions, including autism spectrum disorder (ASD). In this opinion paper we will shortly discuss the challenging nature of autism research then summarize the different neurocognitive frameworks for ASD making the case for a canine model of autism. The translational value of a dog model stems from the recognition that (a) there is a large inter-individual variability in the manifestation of dogs' social cognitive abilities including both high and low phenotypic extremes; (b) the phenotypic similarity between the dog and human symptoms are much higher than between the rodent and human symptoms; (c) the symptoms are functionally analogous to the human condition; and (d) more likely to have similar etiology. This article is categorized under: Psychology > Comparative Psychology Cognitive Biology > Evolutionary Roots of Cognition.


Asunto(s)
Trastorno Autístico/fisiopatología , Conducta Animal , Evolución Biológica , Modelos Animales de Enfermedad , Animales , Perros , Interacción Gen-Ambiente , Humanos , Neurociencias , Conducta Social
17.
Front Behav Neurosci ; 13: 295, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-32009915

RESUMEN

Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function, repetitive and restricted behaviors. Valproic acid (VPA) was reported to increase the prevalence of ASD in humans as a consequence of its use during pregnancy. VPA treatment also induces autistic-like behaviors in the offspring of rats after prenatal exposure; hence it is a preclinical disease model with high translational value. In the present study, our aim was to characterize ASD relevant behaviors of socially housed, individually identified male rats in automated home cages. The natural behavior of rats was assessed by monitoring their visits to drinking bottles in an environment without human influence aiming at reducing interventional stress. Although rodents normally tend to explore their new environment, prenatally VPA-treated rats showed a drastic impairment in initial and long-term exploratory behavior throughout their stay in the automated cage. Furthermore, VPA rats displayed psychogenic polydipsia (PPD) as well as altered circadian activity. In the competitive situation of strict water deprivation controls switched to an uneven resource sharing and only a few dominant animals had access to water. In VPA animals similar hierarchy-related changes were completely absent. While the control rats secured their chance to drink with frequent reentering visits, thereby "guarding" the water resource, VPA animals did not switch to uneven sharing and displayed no evidence of guarding behavior.

18.
Sci Rep ; 9(1): 9225, 2019 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-31239528

RESUMEN

While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown. We combined multimodal MRI (9.4 T) brain assessment of the prenatal rat valproate (VPA) model and correlated immunohistological analysis of the cerebellar Purkinje cell number to address this question. We hypothesized that a suitable functional MRI (fMRI) paradigm might show some altered activity related to disrupted cerebrocerebellar information processing. Two doses of maternal VPA (400 and 600 mg/kg, s.c.) were used. The higher VPA dose induced 3% smaller whole brain volume, the lower dose induced 2% smaller whole brain volume and additionally a focal gray matter density decrease in the cerebellum and brainstem. Increased cortical BOLD responses to whisker stimulation were detected in both VPA groups, but it was more pronounced and extended to cerebellar regions in the 400 mg/kg VPA group. Immunohistological analysis revealed a decreased number of Purkinje cells in both VPA groups. In a detailed analysis, we revealed that the Purkinje cell number interacts with the cerebral BOLD response distinctively in the two VPA groups that highlights atypical function of the cerebrocerebellar circuit loops with potential translational value as an ASD biomarker.


Asunto(s)
Trastorno Autístico/patología , Células de Purkinje/patología , Ácido Valproico/efectos adversos , Animales , Trastorno Autístico/inducido químicamente , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/fisiopatología , Calbindinas/metabolismo , Recuento de Células , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Células de Purkinje/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
19.
Sleep ; 31(11): 1579-85, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19014078

RESUMEN

STUDY OBJECTIVES: Frequently disrupted and restricted sleep is a common problem for many people in our Western society. In the long run, insufficient sleep may have repercussions for health and may sensitize individuals to psychiatric diseases. In this context, we applied an animal model of chronic sleep restriction to study effects of sleep loss on neurobiological and neuroendocrine systems that have been implied in the pathophysiology of depression, particularly the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: Adult rats were exposed to a schedule of chronic partial sleep deprivation allowing them only 4 h of sleep per day. Sleep restriction was achieved by placing the animals in slowly rotating drums. To examine the regulation and reactivity of the HPA axis, blood samples were collected to measure adrenocorticotropin (ACTH) and corticosterone (CORT) responses. MEASUREMENTS AND RESULTS: While one day of restricted sleep had no significant effect on HPA axis stress reactivity, sleep restriction for a week caused a blunted pituitary ACTH response in a conditioned fear paradigm. Despite this lower ACTH response, adrenal CORT release was normal. The blunted pituitary response may be related to reduced sensitivity of serotonin-1A receptors and/or receptors for corticotropin-releasing hormone (CRH), since sleep restricted rats showed similar reductions in ACTH release to direct pharmacological stimulation with a serotonin-1A agonist or CRH. CONCLUSIONS: Chronic sleep restriction may lead to changes in neurotransmitter receptor systems and neuroendocrine reactivity in a manner similar to that seen in depression. This experimental study thus supports the hypothesis that disrupted and restricted sleep may contribute to the symptomatology of psychiatric disorders.


Asunto(s)
Corticosterona/metabolismo , Depresión , Receptores de Corticotropina/metabolismo , Privación de Sueño , Animales , Condicionamiento Psicológico , Hormona Liberadora de Corticotropina/metabolismo , Depresión/epidemiología , Depresión/etiología , Depresión/fisiopatología , Miedo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Privación de Sueño/epidemiología , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismo , Estrés Psicológico/psicología
20.
Brain Res ; 1191: 69-74, 2008 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-18163981

RESUMEN

Adenosine is an important neuromodulator and neuroprotective molecule, which is produced in the brain as a function of neuronal activity, coupling energy expenditure to energy supply. Under conditions of increased need and reduced availability of energy, including hypoxia and prolonged wakefulness, there is an increase in adenosine turnover and adenosine receptor stimulation. The aim of the present study was to examine how repetitive adenosine receptor stimulation affects receptor function and adenosinergic signaling in the brain. Adult male Wistar rats received daily intraperitoneal injections of the adenosine A1 receptor agonist N(6)-cyclopentyladenosine (CPA; 0.25 mg/kg; once per day) and effects on adenosine signaling were established with receptor and G-protein autoradiography. Injections of CPA for 5 consecutive days caused a significant decrease in adenosine A1 receptor numbers in the hippocampus and somatosensory cortex. In contrast, while the amount of adenosine A1 receptor-activated G-proteins was not affected in most regions, a significant increase was found in the somatosensory cortex. On the level of physiological output, CPA-induced hypothermia was significantly attenuated, suggesting a functional desensitization of the A1 receptor system. Taken together, the present findings suggest that repetitive stimulation of the A1 receptors can affect elements of the adenosinergic signaling cascade in the rat brain in a region-specific manner.


Asunto(s)
Hipocampo/metabolismo , Hipotermia/metabolismo , Receptor de Adenosina A1/metabolismo , Transducción de Señal/fisiología , Corteza Somatosensorial/metabolismo , Adenosina/análogos & derivados , Agonistas del Receptor de Adenosina A1 , Análisis de Varianza , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Regulación hacia Abajo/efectos de los fármacos , Proteínas de Unión al GTP/metabolismo , Hipocampo/efectos de los fármacos , Hipotermia/inducido químicamente , Masculino , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Corteza Somatosensorial/efectos de los fármacos , Estadísticas no Paramétricas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA